The primary objective of the research project is to study the mechanisms of action of diabetogenic agents such as streptozotocin and alloxan. Also, methods of antagonizing the pancreotoxic actions of these chemicals are being investigated. The ability of these agents to produce necrotic damage to pancreatic beta cells interferes with their preclinical evaluation and their clinical utility. We have developed an in vitro model for studying the effects of alloxan on pancreatic secretory activity and have found that alloxan-induced changes in pancreatic insulin secretion in vitro correspond to changes seen in vivo after the administration of a diabetogenic dose. This new model will be employed to study the in vitro interaction between alloxan and various agents which are known to antagonize the diabetogen in vivo. Studies on the in vivo interactions between alloxan and structurally related chemicals will be continued. It is hoped that these studies will provide structure-activity relationship information which will lead to an understanding of chemical requirements for pancreatic activity. It is felt that selective antagonism of the pancreatic effects of cancer chemotherapeutic agents will facilitate their preclinical evaluation as well as their clinical utility.